Remnant lipoproteins are formed from chylomicrons and very low density lipoproteins (VLDL) (after their triglycerides are hydrolyzed by the lipoprotein lipase) and are rich in cholesterol and apolipoprotein E. These remnant lipoproteins accumulate in plasma of human subjects with type III hyperlipoproteinemia and all animal species which develop hypercholesterol and atherosclerosis in response to cholesterol feeding. The liver plays a major role in the catabolism of these remnant lipoproteins. The proposed studies will investigate the uptake of normal and cholesterol-rich VLDL (from cholesterol-fed rabbits) in a non-recirculating isolated liver perfusion system, which has been developed and validated in our lab. Using a rabbit liver system, we will determine if the uptake of normal or cholesterol-rich VLDL (from cholesterol-fed animals) is related to the amount of beta-VLDL or remnants present. The effect of concentration of these lipoproteins upon their uptake by the liver will be determined in order to investigate if such uptake is due to a single specific mechanism. Using electron microscopy and radioautography, we will determine which type of cell and subcellular organell is involved in the uptake and catabolism of remnant lipoproteins. Immunofluorescence studies will be conduted to localize apo B and apo E in liver cells to determine if these are processed separately. A major portion of these studies will be devoted to determining the determinant or structure responsible for such uptake of remnants by the liver. Finally, we will investigate the effect of exogenous estrogens upon the hepatic remnant removal process by treating the donor animal with depoestradiol and further investigate the time course of such effect (as seen in preliminary studies).